Granulates suitably pellets as molded particles serve in the pharmaceutical industry mainly as intermediate products for tableting. The molding should thus lead to a free flowing, granular and dust free product, that, because of its uniformity, improves the technological processing and dosage exactness. Furthermore, pellets have, as modern multiple unit dosage forms, for example charged to hard gelatin capsules as opposed to single unit dosage forms such as tablets or dragees, a plurality of advantages:
They are evenly distributed in the gastrointestinal tract.
Because of their small size as opposed to the monolithic dosage forms they result in shorter stomach residence times, more particularly so in gastric juice resist coated dosage forms.
They dissolve more quickly in the gastrointestinal tract as single aggregates in contrast to a compressed table which must first dissociate into its granulated portions.
Pellets with different active substance release rate can be provided in a single dose in mixed form.
Nevertheless, all processes of the state of the art have the basic problem of the need to provide form to powdery crystalline, active and inactive ingredients to utilizable granulates (pellets) as molded particles.
One must differentiate therein between associating and dissociating procedures. It is common to all processes that for a long time it has been possible to arrive at granulates suitably pellets as molded particles only via a plurality of expensive partial steps.
In the dissociative procedures, summarized in simplified form, the pharmaceutically active and inactive ingredients are diminuated through sieves to a uniform grain size and then mixed. Thereafter follows dry or damp granulation in which the powder mixture is aggregated and subsequently reduced in size to granular grains. In the next step, if necessary, there is drying and again sieving.
In associatively constructed granulates, the powder formed pharmaceuticals and inactive ingredients are formed into granulated grains in a controlled process (for example Vortex layer process) under the continual addition of a granulating fluid under the simultaneous drying.
During a subsequent, special rounding procedure (for example, Marumerizer.RTM.) round, spherical granulate particles (pellets) are achieved. The disadvantage hereby is that in rounding out of already created, unformed granulated particles, a mass of substance containing the pharmaceutical is lost and cannot be directly recycled into the granulation process. This of course creates a expense and clean-up technological problem. At the same time mechanical forming leads to a product of uneven size.
Special pelleting techniques are for example the associative dry pelleting through compacting and the Vortex layer granulation which give very unsatisfactory results with respect to form and mechanical stability of the pellets.
All these production processes require technologically expensive multistep procedures. They are characterized by a plurality of technological process parameters, for example temperature, moisture content, homogeneity of the mixtures and so on.
Furthermore, in all granulation and pelleting procedures the provision of a whole row of inactive ingredients is required. Thus, for example, binding materials or granulating fluids must be provided in order to bring the powdery substrate into a solid compact and workable form. Most knowledge is required about the physico-chemical conditions, for example heat of solution, solubility or crystal formation tendency and considerable experience in utilizing these materials is necessary in order to be able to judge the coworking of these additive materials with each other and with the pharmaceutically active substance in conjunction with all of the process parameters.
Thus, the pharmaceutical requirements for a granulate (pellets) are often only fulfilled by empirical experiments in dependence upon the pharmaceutically active material to be processed and the dosage form to be formulated therefrom.
It is thus understandable that the maintenance of constant production requirements in these complex processes is very difficult. Thus, it is because the plurality of parameters which must be considered in the known production processes, and despite high development and optimization expenditures, it is not possible to find a suitable process for every pharmaceutically active material.
When one considers the pellets or granulates formed in accordance with the state of the art and furthermore the biopharmaceutical aspects thereof, so it must be recognized that the pharmaceutically active materials of these aggregated molded bodies are only available to the organism after disaggretation and subsequent release. The plurality of substantially distinguishable holding and binding forces in granulates clarifies this problem. Because of the utilization of hardening binders in the drying step (damp granulation) or via sintering or melt-binding under the influence of pressure (dry granulation), solid are formed, whose binding forces must be overcome in the organism in order for the pharmaceutical material even to be released in active form.
Every production step in the process of the state of the art can act as an undesirable influence on the release of the active substance and thus its bioavailability.
The present invention thus has the task to suggest new molded particles, a process for their preparation as well as mixtures, which, on the grounds of their structure and composition improve the bioavailability and compatibility of the active substances, are shelf stable, exactly dosable, providable as single or multiple unit doses and are ecologically compatible, and can be produced in a simple and economical manner. In such a way that the active materials are processed in a protected way and thus the disadvantages of the state of the art overcome.